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Literature summary for 3.4.11.1 extracted from
- Structural characterization of acidic M17 leucine aminopeptidases from the TriTryps and evaluation of their role in nutrient starvation in Trypanosoma brucei (2017), mSphere, 2, e00226-17 .
Application
| Application | Comment | Organism |
|---|---|---|
| drug development | LAP-A as a potential drug target in Trypanosoma brucei | Trypanosoma brucei brucei |
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| gene lap, recombinant expression of His-tagged enzyme in Escherichia coli | Leishmania major |
| gene lap, recombinant expression of His-tagged enzyme in Escherichia coli | Trypanosoma cruzi marinkellei |
| gene lap, recombinant expression of His-tagged enzyme in Escherichia coli, overexpression of c-Myc-tagged LAP-A in Trypanosoma brucei parasites cytosol | Trypanosoma brucei brucei |
Crystallization (Commentary)
| Crystallization (Comment) | Organism |
|---|---|
| purified recombinant His-tagged enzyme LmLAP-A, in the presence of Mn2+, X-ray diffraction structure determination and analysis at 2.5 A resolution, molecular replacement, modelling | Leishmania major |
| purified recombinant His-tagged enzyme LmLAP-A, X-ray diffraction structure determination and analysis at 2.5 A resolution, molecular replacement, modelling. TcLAP-A crystallizes exclusively under citratecontaining conditions, which leads to the absence of one or both Mn2x02 ions from the active site and hence no electron density for the inhibitors | Trypanosoma cruzi marinkellei |
| purified recombinant His-tagged enzyme TbLAP-A in complex with inhibitor bestatin, in the presence of ZnCl2 and Mn2+, X-ray diffraction structure determination and analysis, molecular replacement, modelling | Trypanosoma brucei brucei |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| additional information | RNA interference (RNAi), double knockout (dKO), and overexpression of the protein in bloodstream form (BF) and procyclic form (PF) Trypanosoma brucei subsp. brucei parasites in culture. RNAi-mediated depletion of LAP-A, phenotype, overview | Trypanosoma brucei brucei |
| additional information | RNAi-mediated depletion of LAP-A, phenotype, overview | Leishmania major |
| additional information | RNAi-mediated depletion of LAP-A, phenotype, overview | Trypanosoma cruzi marinkellei |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| actinonin | 3-((1-((2-[hydroxymethyl]-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamoyl)octanohydroxaminic acid, actinonin in LmLAP-A is coordinated by the Mn2+ ions and hydrogen bonds | Leishmania major |  |
| actinonin | 3-((1-((2-[hydroxymethyl]-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamoyl)octanohydroxaminic acid. Actinonin in TbLAP-A is coordinated by the Mn2+ ions and hydrogen bonds, overview | Trypanosoma brucei brucei | |
| actinonin | 3-((1-((2-[hydroxymethyl]-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamoyl)octanohydroxaminic acid | Trypanosoma cruzi marinkellei | |
| amastatin | - |
Trypanosoma cruzi marinkellei | |
| bestatin | - |
Trypanosoma brucei brucei | |
| additional information | the structures of LAP-A in its apo and holo forms and in complex with inhibitors are practically identical. The apo LmLAP-A structure shows a completely ordered active site independent of metal or ligand binding | Leishmania major | |
| additional information | the structures of LAP-A in its apo and holo forms and in complex with inhibitors are practically identical | Trypanosoma brucei brucei | |
| additional information | the structures of LAP-A in its apo and holo forms and in complex with inhibitors are practically identical. The apo TcLAP-A structure shows a completely ordered active site independent of metal or ligand binding | Trypanosoma cruzi marinkellei |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytoplasm | - |
Leishmania major | 5737 | - |
| cytoplasm | - |
Trypanosoma brucei brucei | 5737 | - |
| cytoplasm | - |
Trypanosoma cruzi marinkellei | 5737 | - |
| kinetoplast | - |
Leishmania major | 20023 | - |
| kinetoplast | - |
Trypanosoma brucei brucei | 20023 | - |
| kinetoplast | - |
Trypanosoma cruzi marinkellei | 20023 | - |
| additional information | in procyclic cells, LAP-A is equally distributed throughout the cytoplasm, yet upon starvation, it relocalizes in particles that concentrate in the perinuclear region. Effect of nutritional starvation on LAP-A subcellular localization | Leishmania major | - |
- |
| additional information | in procyclic cells, LAP-A is equally distributed throughout the cytoplasm, yet upon starvation, it relocalizes in particles that concentrate in the perinuclear region. Effect of nutritional starvation on LAP-A subcellular localization | Trypanosoma brucei brucei | - |
- |
| additional information | in procyclic cells, LAP-A is equally distributed throughout the cytoplasm, yet upon starvation, it relocalizes in particles that concentrate in the perinuclear region. Effect of nutritional starvation on LAP-A subcellular localization | Trypanosoma cruzi marinkellei | - |
- |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Mn2+ | active site-bound | Leishmania major | |
| additional information | metalloprotease, metal coordination in the active site and apo LAP-A, overview | Leishmania major | |
| additional information | metalloprotease, metal coordination in the active site and apo LAP-A, overview | Trypanosoma cruzi marinkellei | |
| additional information | metalloprotease, metal coordination in the active site and apo LAP-A, overview. The metal-free apo TbLAP-A form shows a disordered active-site loop (aa 293 to 305) | Trypanosoma brucei brucei | |
| Zn2+ | required | Leishmania major | |
| Zn2+ | required | Trypanosoma brucei brucei | |
| Zn2+ | required | Trypanosoma cruzi marinkellei | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Leishmania major | Q7KF27 | - |
- |
| Trypanosoma brucei brucei | Q6Q833 | - |
- |
| Trypanosoma cruzi marinkellei | H2CS62 | - |
- |
Purification (Commentary)
| Purification (Comment) | Organism |
|---|---|
| recombinant His-tagged enzyme from Escherichia coli by nickel affinity chromatography and gel filtration | Leishmania major |
| recombinant His-tagged enzyme from Escherichia coli by nickel affinity chromatography and gel filtration | Trypanosoma brucei brucei |
| recombinant His-tagged enzyme from Escherichia coli by nickel affinity chromatography and gel filtration | Trypanosoma cruzi marinkellei |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| L-Leu 7-amido-4-methylcoumarin + H2O | - |
Leishmania major | L-Leu + 7-amino-4-methylcoumarin | - |
? | |
| L-Leu 7-amido-4-methylcoumarin + H2O | - |
Trypanosoma brucei brucei | L-Leu + 7-amino-4-methylcoumarin | - |
? | |
| L-Leu 7-amido-4-methylcoumarin + H2O | - |
Trypanosoma cruzi marinkellei | L-Leu + 7-amino-4-methylcoumarin | - |
? | |
| additional information | little or no activity against L-Val 7-amido-4-methylcoumarin and L-Pro 7-amido-4-methylcoumarin is detected | Leishmania major | ? | - |
? | |
| additional information | little or no activity against L-Val 7-amido-4-methylcoumarin and L-Pro 7-amido-4-methylcoumarin is detected | Trypanosoma brucei brucei | ? | - |
? | |
| additional information | little or no activity against L-Val 7-amido-4-methylcoumarin and L-Pro 7-amido-4-methylcoumarin is detected | Trypanosoma cruzi marinkellei | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| homohexamer | - |
Leishmania major |
| homohexamer | - |
Trypanosoma brucei brucei |
| homohexamer | the hexamer is the most abundant species, while as the concentration was lowered, the proportion of trimers increases | Trypanosoma cruzi marinkellei |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| acidic M17 leucine aminopeptidase | - |
Leishmania major |
| acidic M17 leucine aminopeptidase | - |
Trypanosoma brucei brucei |
| acidic M17 leucine aminopeptidase | - |
Trypanosoma cruzi marinkellei |
| LAP-A | - |
Leishmania major |
| LAP-A | - |
Trypanosoma brucei brucei |
| LAP-A | - |
Trypanosoma cruzi marinkellei |
| leucine aminopeptidase | - |
Leishmania major |
| leucine aminopeptidase | - |
Trypanosoma brucei brucei |
| leucine aminopeptidase | - |
Trypanosoma cruzi marinkellei |
| LmLAP-A | - |
Leishmania major |
| TbLAP-A | - |
Trypanosoma brucei brucei |
| TcLAP-A | - |
Trypanosoma cruzi marinkellei |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | the leucine aminopeptidase (LAP) is a member of the M17 family of metalloproteases | Leishmania major |
| evolution | the leucine aminopeptidase (LAP) is a member of the M17 family of metalloproteases | Trypanosoma brucei brucei |
| evolution | the leucine aminopeptidase (LAP) is a member of the M17 family of metalloproteases | Trypanosoma cruzi marinkellei |
| additional information | structure comparisons of plasmodial LAP-As from Trypanosoma brucei subsp. brucei, Trypanosoma cruzi, and Leishmania major, overview. Structural differences in LmLAP-A compared to TbLAP-A and TcLAP-A are mostly located in the loop regions | Leishmania major |
| additional information | structure comparisons of plasmodial LAP-As from Trypanosoma brucei subsp. brucei, Trypanosoma cruzi, and Leishmania major, overview. Structural differences in LmLAP-A compared to TbLAP-A and TcLAP-A are mostly located in the loop regions | Trypanosoma brucei brucei |
| additional information | structure comparisons of plasmodial LAP-As from Trypanosoma brucei subsp. brucei, Trypanosoma cruzi, and Leishmania major, overview. Structural differences in LmLAP-A compared to TbLAP-A and TcLAP-A are mostly located in the loop regions | Trypanosoma cruzi marinkellei |
| physiological function | the enzyme is not required for the growth of this parasite either in vitro or in vivo. Role of LAP-A in leucine starvation, overview | Leishmania major |
| physiological function | the enzyme is not required for the growth of this parasite either in vitro or in vivo. Role of LAP-A in leucine starvation, overview | Trypanosoma brucei brucei |
| physiological function | the enzyme is not required for the growth of this parasite either in vitro or in vivo. Role of LAP-A in leucine starvation, overview | Trypanosoma cruzi marinkellei |
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